Long-Term Imaging Reveals a Circadian Rhythm of Intracellular Chloride in Neurons of the Suprachiasmatic Nucleus

The mammalian circadian clock located in the suprachiasmatic nucleus (SCN) produces robust daily rhythms including rest–wake. SCN neurons synthesize and respond to γ-aminobutyric acid (GABA), but its role remains unresolved. We tested the hypothesis that γ2- and δ-subunits of the GABA A receptor in the SCN differ in their regulation of synchrony among circadian cells. We used two approaches: 1) shRNA to knock-down (KD) the expression of either γ2 or δ subunits in the SCN or 2) knock-in mice harboring a point mutation in the M2 domains of the endogenous GABA A γ2 or δ subunits. KD of either γ2 or δ subunits in the SCN increased daytime running and reduced nocturnal running by reducing their circadian amplitude by a third. Similarly, δ subunit knock-in mice showed decreased circadian amplitude, increased duration of daily activity, and decreased total daily activity. Reduction, or mutation of either γ2 or δ subunits halved the synchrony among, and amplitude of, circadian SCN cells as measured by firing rate or expression of the PERIOD2 protein, in vitro. Surprisingly, overexpression of the γ2 subunit rescued these phenotypes following KD or mutation of the δ subunit, and overexpression of the δ subunit rescued deficiencies due to γ2 subunit KD or mutation. We conclude that γ2 and δ GABA A receptor subunits play similar roles in maintaining circadian synchrony in the SCN and amplitude of daily rest–wake rhythms, but that modulation of their relative densities can change the duration and amplitude of daily activities.

show abstract

Ion dynamics and the regulation of circadian cellular physiology

Stangherlin

2023

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

Circadian rhythms in physiology and behaviour allow organisms to anticipate the daily environmental changes imposed by the rotation of our planet around its axis. Although these rhythms eventually manifest at the organismal level, a cellular basis for circadian rhythms has been demonstrated. Significant contributors to these cell-autonomous rhythms are daily cycles in gene expression and protein translation. However, recent data revealed cellular rhythms in other biological processes, including ionic currents, ion transport, and cytosolic ion abundance. Circadian rhythms in ion currents sustain circadian variation in action potential firing rate, which coordinates neuronal behaviour and activity. Circadian regulation of metal ions abundance and dynamics is implicated in distinct cellular processes, from protein translation to membrane activity and osmotic homeostasis. In turn, studies showed that manipulating ion abundance affects the expression of core clock genes and proteins, suggestive of a close interplay. However, the relationship between gene expression cycles, ion dynamics and cellular function is still poorly characterised. In this review, I will discuss the mechanisms that generate ion rhythms, the cellular functions they govern and how they feed back to regulate the core clock machinery.

show abstract

scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.

Contact Info

hi@scite.ai

10624 S. Eastern Ave., Ste. A-614

Henderson, NV 89052, USA

Blog Terms and Conditions API Terms Privacy Policy Contact Cookie Preferences Do Not Sell or Share My Personal Information

Made with 💙 for researchers

Part of the Research Solutions Family.

Long-Term Imaging Reveals a Circadian Rhythm of Intracellular Chloride in Neurons of the Suprachiasmatic Nucleus

Cited by 4 publications

References 87 publications

The importance of ligand gated ion channels in sleep and sleep disorders

The importance of ligand gated ion channels in sleep and sleep disorders

GABA _A receptor subunit composition regulates circadian rhythms in rest–wake and synchrony among cells in the suprachiasmatic nucleus

Ion dynamics and the regulation of circadian cellular physiology

Contact Info

Product

Resources

About

Long-Term Imaging Reveals a Circadian Rhythm of Intracellular Chloride in Neurons of the Suprachiasmatic Nucleus

Cited by 4 publications

References 87 publications

The importance of ligand gated ion channels in sleep and sleep disorders

The importance of ligand gated ion channels in sleep and sleep disorders

GABA A receptor subunit composition regulates circadian rhythms in rest–wake and synchrony among cells in the suprachiasmatic nucleus

Ion dynamics and the regulation of circadian cellular physiology

Contact Info

Product

Resources

About

GABA _A receptor subunit composition regulates circadian rhythms in rest–wake and synchrony among cells in the suprachiasmatic nucleus